Immunotherapy with histamine dihydrochloride and low‐dose interleukin‐2 favors sustained lymphocyte recovery in acute myeloid leukemia

Hallner, Alexander; Aurelius, Johan; Thorén, Fredrik B.; Sander, Frida Ewald; Brüne, Martin; Hellstrand, Kristoffer; Martner, Anna

doi:10.1111/ejh.12454

Cited by 4 publications

(6 citation statements)

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“…6D ). 39 The increment of lymphocyte counts between treatment cycles in this phase III trial likely reflected an accumulation of CD16 + NK cells, since CD16 + NK cells accounted for the majority (median 53%) of the lymphocyte increment between the onset of cycles 1 and 3 in the current phase IV Re:Mission trial using the identical treatment regimen. In agreement with the results in the Re:Mission trial, the lymphocyte induction between the onset of treatment and the start of cycle 3 in HDC/IL-2 treated patients in the phase III trial was predictive of LFS and OS ( Figs.…”

Section: Resultsmentioning

confidence: 79%

“…The validity of the latter finding was supported by post-hoc analyses of the results of a previous phase III trial, where induction of lymphocytes between cycles 1 and 3 was significantly associated with LFS and OS in patients randomized to receive HDC/IL-2 but not in untreated control patients. 39 Since CD56 bright NK cells are assumed to be the immediate precursors of CD16 + NK cells, 19-22 we hypothesize from these findings that the anti-leukemic efficacy of HDC/IL-2 immunotherapy results, at least in part, from initial activation and expansion of CD56 bright NK cells that subsequently differentiate into cytotoxic CD16 + cells. The finding of a significantly increased ratio of CD16 + to CD56 bright NK cell counts between the first days of cycles 1 and 3 supports that CD56 bright cells may have differentiated into cytotoxic CD16 + cells during immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia

et al. 2015

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In a phase IV trial, 84 patients (age 18–79) with acute myeloid leukemia (AML) in first complete remission (CR) received cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose human recombinant interleukin 2 (IL-2) for 18 months to prevent leukemic relapse. During cycles, the treatment resulted in expansion of CD56bright (CD3−/16−/56bright) and CD16+ (CD3−/16+/56+) natural killer (NK) cells in the blood along with increased NK cell expression of the natural cytotoxicity receptors (NCRs) NKp30 and NKp46. Multivariate analyses correcting for age and risk group demonstrated that high CD56bright NK cell counts and high expression of NKp30 or NKp46 on CD16+ NK cells independently predicted leukemia-free survival (LFS) and overall survival (OS). Our results suggest that the dynamics of NK cell subsets and their NCR expression may determine the efficiency of relapse-preventive immunotherapy in AML.

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Section: Resultsmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Role of natural killer cell subsets and natural cytotoxicity receptors for the outcome of immunotherapy in acute myeloid leukemia

et al. 2015

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“…The ability of HDC to protect immune cells with tumor-killing capacity has been proposed to contribute to the clinical benefit of HDC-based therapy in AML ( 8 , 19 , 20 ). Anti-leukemic properties of HDC may alternatively or additionally relate to its pro-differentiating effects on myeloid cells.…”

Section: Introductionmentioning

confidence: 99%

Anti-Leukemic Properties of Histamine in Monocytic Leukemia: The Role of NOX2

et al. 2018

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In patients with acute myeloid leukemia (AML), treatment with histamine dihydrochloride (HDC) and low-dose IL-2 (HDC/IL-2) in the post-chemotherapy phase has been shown to reduce the incidence of leukemic relapse. The clinical benefit of HDC/IL-2 is pronounced in monocytic forms of AML, where the leukemic cells express histamine type 2 receptors (H2R) and the NAPDH oxidase-2 (NOX2). HDC ligates to H2Rs to inhibit NOX2-derived formation of reactive oxygen species, but details regarding the anti-leukemic actions of HDC remain to be elucidated. Here, we report that human NOX2+ myelomonocytic/monocytic AML cell lines showed increased expression of maturation markers along with reduced leukemic cell proliferation after exposure to HDC in vitro. These effects of HDC were absent in corresponding leukemic cells genetically depleted of NOX2 (NOX2−/−). We also observed that exposure to HDC altered the expression of genes involved in differentiation and cell cycle progression in AML cells and that these effects required the presence of NOX2. HDC promoted the differentiation also of primary monocytic, but not non-monocytic, AML cells in vitro. In a xenograft model, immunodeficient NOG mice were inoculated with wild-type or NOX2−/− human monocytic AML cells and treated with HDC in vivo. The administration of HDC reduced the in vivo expansion of NOX2+/+, but not of NOX2−/− human monocytic AML cells. We propose that NOX2 may be a conceivable target in the treatment of monocytic AML.

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“…36 Patients treated with HDC/IL2 and displaying lymphocyte induction between cycles 1 and 3 and between cycles 1 and 4 had an LFS of 57%, whereas patients with no lymphocyte induction had an LFS of 27%. 39 Together, these results suggest that IL2 may be beneficial in some patients, particularly if combined with HDC. One of the main limitations of the ELAM02 trial was the withdrawal of 41% of the eligible patients, mostly due to patient/ parental refusal, or medical reasons.…”

Section: Discussionmentioning

confidence: 85%